Substituted thiazolo[3,2-a]pyrimidines and process for their preparation

ABSTRACT

Pharmacologically active thiazolo[3,2-a]pyrimidines of the formula ##STR1## wherein A is a bond between the α and β-carbon atoms or (--CH 2  --) group; R 1  and R 2  represent hydrogen or halogen, C 1  -C 4  alkyl, cyano, CF 3 , thienyl, pyridyl, biphenyl, naphtyl, phenyl optionally substituted, ##STR2## wherein R&#39; and R&#34; are hydrogen or alkyl; R 3  represents hydrogen, halogen, alkyl, OH, formyloxy, alkanoyloxy, alkenyloxy; R 4  represents pyridyl optionally substituted by alkyl. The compounds have antiinflammatory, antiulcerogenic and anti-gastric secretory activity.

The present invention relates to substituted thiazolo[3,2-a]pyrimidines,to a process for their preparation and to pharmaceutical compositionscontaining them. The invention provides compounds having the followinggeneral formula (I) ##STR3## wherein

A completes a bond, thereby providing a double bond between the α- andβ-carbon atoms, or

A represents a --CH₂ -- group, thereby providing a cyclopropane ringincluding the α- and β-carbon atoms;

each of R₁ and R₂ independently represents:

(a) a hydrogen or a halogen atom;

(b) C₁ -C₄ alkyl, cyano or trifluoromethyl;

(c) thienyl, pyridyl, biphenyl or naphtyl;

(d) a phenyl group, unsubstituted or substituted by 1 to 3 substituentschosen from halogen, C₁ -C₄ alkyl, hydroxy, C₁ -C₄ alkoxy, formyloxy, C₂-C₈ alkanoyloxy, trifluoromethyl, nitro, amino, formylamino, C₂ -C₈alkanoylamino;

(e) a phenyl group substituted by one or two C₁ -C₄ alkylenedioxygroups, wherein the oxygen atoms are linked to two adjacent carbon atomsof the phenyl ring;

(f) a group ##STR4## wherein each of R' and R" independently representsa hydrogen atom or a C₁ -C₄ alkyl group;

R₃ represents:

(a') a hydrogen or halogen atom;

(b') C₁ -C₄ alkyl;

(c') hydroxy, formyloxy or C₂ -C₈ alkanoyloxy;

(d') C₁ -C₄ alkoxy or C₃ -C₄ alkenyloxy;

R₄ represents:

(a") a pyridyl group, which may be unsubstituted or substituted by C₁-C₄ alkyl;

(b") a group ##STR5## wherein R₅ represents a hydrogen atom or a C₁ -C₄alkyl group;

(c") a group of formula ##STR6## wherein each of R₆, R₇ and R₈independently represents a hydrogen or a halogen atom; a hydroxy group;a C₁ -C₆ alkoxy group unsubstituted or substituted by C₁ -C₄dialkylamino group; a C₁ -C₄ alkyl group; formyloxy or a C₂ -C₈alkanoyloxy group; a --NO₂ group or a group ##STR7## wherein each of R₉and R₁₀ independently represents a hydrogen atom, a C₁ -C₄ alkyl group,formyl or a C₂ -C₈ alkanoyl group;

(d") a thiazolyl group, which may be unsubstituted or substituted by C₁-C₄ alkyl.

The compounds of the invention include also the pharmaceuticallyacceptable salts of the compounds of formula (I) the metabolites andmetabolic precursors of the compounds of formula (I), as well as allpossible isomers (e.g. cis or trans isomers and optical isomers) and themixtures thereof. Preferably the ##STR8## moiety, wherein A and R₄ areas defined above, is in the trans configuration. The alkyl, alkoxy,alkenyloxy, alkanoyl and alkanoyloxy groups may be branched or straightchain groups. When R₁ and/or R₂ are a C₁ -C₄ alkyl group, they arepreferably a C₁ -C₂ alkyl group.

When R₁ and/or R₂ are a phenyl ring substituted as defined above, thephenyl ring is preferably substituted by one or two substituents chosenfrom chlorine, fluorine, methyl, methoxy, hydroxy, C₁ -C₂ alkylenedioxyand amino.

When one or more of R₁, R₂ and R₃ are a halogen atom, they arepreferably chlorine or bromine.

When R₃ is C₁ -C₄ alkoxy, it is preferably methoxy or ethoxy. When R₃ isC₁ -C₄ alkyl, it is preferably methyl, ethyl or propyl; When one or bothof R₉ and R₁₀ is a C₂ -C₈ alkanoyl group, it is for example acetyl,propionyl, butyryl, valeryl and isovaleryl, preferably it is acetyl andpropionyl. When R₄ is substituted pyridyl, it is preferably substitutedby a methyl group.

When R₄ is substituted thiazolyl, it is preferably substituted by amethyl group. When R₅ is a C₁ -C₄ alkyl group it is preferably a methylor ethyl group. When one or more of R₃, R₆, R₇ and R₈ represents a C₂-C₈ alkanoyloxy group, it is for example acetoxy, propionyloxy andbutyryloxy; preferably it is acetoxy.

Preferably R' and R" are hydrogen or a C₁ -C₂ alkyl group. When one ormore of R₆, R₇ and R₈ is a C₁ -C₆ alkoxy group, it is preferably amethoxy or an ethoxy group. When one or more of R₆, R₇ and R₈ is a C₁-C₄ alkyl group, it is preferably a methyl group. When one or more ofR₆, R₇ and R₈ is a halogen atom, it is preferably chlorine, fluorine oriodine. Preferred compounds of the invention are the compounds offormula (I) wherein A is as defined above; R₁ is hydrogen, C₁ -C₂ alkyl,trifluoromethyl, carboxymethyl, pyridyl, biphenyl, naphtyl or phenyl,the phenyl being unsubstituted or substituted as defined above; R₂ ishydrogen, chlorine, bromine, C₁ -C₂ alkyl, cyano, or phenyl,unsubstituted or substituted as defined above; R₃ is hydrogen, chlorine,bromine, C₁ -C₃ alkyl or C₁ -C₂ alkoxy; and R₄ represents (a"") apyridyl group unsubstituted or substituted by a methyl group; (b"") aphenyl group unsubstituted or substituted by one or two substituentsselected from C₁ -C₂ alkyl, chlorine, iodine, hydroxy, C₁ -C₃ alkoxy,amino, acetylamino and acetoxy; (c"") a thiazolyl group, unsubstitutedor substituted by C₁ -C₂ alkyl; and the pharmaceutically acceptablesalts thereof. Examples of pharmaceutically acceptable salts are eitherthose with inorganic bases, such as sodium, potassium, calcium andaluminium hydroxides or with organic bases, such as lysine,triethylamine, triethanolamine, dibenzylamine, methylbenzylamine,di-(2-ethyl-hexyl)-amine, piperidine, N-ethylpiperidine,N,N-diethylaminoethylamine, N-ethylmorpholine, β-phenethylamine,N-benzyl-β-phenethylamine, N-benzyl-N,N-dimethylamine and the otheracceptable organic amines, as well as the salts with inorganic acids,e.g. hydrochloric, hydrobromic sulphuric and nitric acids and withorganic acids, e.g. citric, tartaric, maleic, malic, fumaric,methanesulphonic and ethanesulphonic acids.

Examples of particularly preferred compounds of the invention are:

7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

7-trans-[2-(4-methyl-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methoxy-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

2-cyano-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

2-chloro-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

2-chloro-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

2-chloro-6-methoxy-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

2-chloro-6-methyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3,6-dimethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

2,3,6-trimethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-2-phenyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-ethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-7-trans-[2-(2-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-7-trans-[2-(6-methyl-2-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-7-trans-[2-(4-methyl-phenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-7-trans-[2-(6-methyl-2-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-7-trans-[2-(2-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-7-trans-(2-phenyl-ethenyl)-5H-thiazolo[3,2-a]pyrimidine-5-one;

2,6-dichloro-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-methyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-2,3-dimethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-trifluoromethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-phenyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(4-fluoro-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(4-chloro-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(4-methyl-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(2-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(3-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(4-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(2-thienyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(2-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(3-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(4-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-7-trans-[2-(3-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

3-(4-amino-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-phenyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(4-fluoro-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(4-chloro-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(4-methyl-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(3-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(4-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(3,4-dimethoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(3,4-ethylenedioxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(4-biphenylyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(2-naphtyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(2-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(3-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(4-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

2-methyl-3-phenyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(4-N-acetyl-amino-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

7-trans-[2-(3-pyridyl)-ethenyl]-3-(2-thienyl)-5H-thiazolo[3,2-a]pyrimidine-5-one,

and the pharmaceutically accpetable salts thereof.

The compounds of formula (I) can be obtained by a process comprising:

(a) reacting a compound of formula (II) ##STR9## wherein R₁, R₂ and R₃are as defined above, or a salt thereof, with an aldehyde of formula(III)

    R.sub.4 --CHO                                              (III)

wherein R₄ is as defined above, so obtaining compound of formula (I)wherein A is a bond; or

(b) reacting a compound of formula (IV) ##STR10## wherein R₁, R₂ and R₃are as defined above, Q may be aryl or C₁ -C₆ alkyl and Y.sup.(-)represents an acidic anion, with an aldehyde of formula (III) as definedabove, so obtaining compounds of formula (I) wherein A is bond; or

(c) reacting a compound of formula (V) ##STR11## wherein R₁, R₂ and R₃are as defined above, with a compound of formula (VI)

    R.sub.4 --CH.sub.2 --P.sup.(+) (Q).sub.3 Y.sup.(-)         (VI)

wherein R₄, Q and Y.sup.(-) are as defined above, or alternatively witha compound of formula (VII) ##STR12## wherein R₄ is as defined above andR₁₁ is C₁ -C₄ alkyl, so obtaining in both cases compounds of formula (I)wherein

A is a bond; or

(d) cyclopropanating a compound of formula (VIII) ##STR13## wherein R₁,R₂, R₃ and R₄ are as defined above, so obtaining compounds of formula(I) wherein A is a --CH₂ -- group; and, if desired, converting acompound of formula (I) into another compound of formula (I) and/or ifdesired, converting a compound of formula (I) into pharmaceuticallyacceptable salt thereof and/or, if desired, converting a salt into afree compound and/or, if desired, separating a mixture of isomers intothe single isomers.

The acidic anion Y.sup.(-) in the compounds of formula (IV) and (VI) is,for example, an acidic anion derived from a hydrohalic acid, preferablyderived from hydrochloric or hydrobromic acid.

When Q in the compounds of formula (IV) and (VI) is aryl, it ispreferably phenyl; and when Q is C₁ -C₆ alkyl, it is preferably ethyl.

The reaction of a compound of formula (II) or a salt thereof with analdehyde of formula (III) is preferably carried out in the presence of abasic condensing agent such as sodium ethoxide, sodium methoxide, sodiumhydride, sodium amide or sodium hydroxide, in a solvent selected, e.g.,from the group consisting of methanol, ethanol, isopropanol, dioxane,water and their mixtures, at a temperature preferably ranging betweenabout 0° C. and 120° C.

The reaction between a compound of formula (IV) and an aldehyde offormula (III) as well as the reaction of a compound of formula (V) witha compound of formula (VI) or with a compound of formula (VII), may, forexample, be carried out by treatment with a base such asdimethylsulphinyl carbanion or sodium methoxide or sodium hydride orpotassium terbutoxide or with an alkyl lithium derivative, preferablywith methyl lithium or butyl lithium or phenyl lithium, in an organicsolvent such as dichloromethane, dichloroethane, benzene, toluene,tetrahydrofuran, dimethylsulfoxide, dimethylformamide, dimethylacetamideor their mixtures at a temperature varying from about 0° C. about 100°C.

The cyclopropanation of a compound of formula (VIII) may be carried out,for example, by reaction with dimethylsulphoxonium methylide (preparede.g. according to the method described in J. Chem. Soc., 1967, 2495),operating in an inert organic solvent selected, e.g., from the groupconsisting of dimethylformamide, dimethylsulfoxide, dioxane and theirmixtures at a temperature ranging preferably between about 0° C. andabout 50° C. Preferably 1-3 moles, in particular 1-1.5 moles, of thereagent are used for one mole of the compound of formula (VIII).

A compound of formula (I) may be converted, as stated above, intoanother compound of formula (I) by known methods; for example, freehydroxy groups, may be etherified by reacting with a suitable alkylhalide in the presence of a base such as NaOH, KOH, Na₂ CO₃, NaH, NaNH₂,sodium methoxide, K₂ CO₃ or sodium ethoxide, in a solvent selected fromthe group consisting, for example, of methanol, ethanol, dioxane,acetone, dimethylformamide, hexamethylphosphorotriamide,tetrahydrofuran, water and their mixtures at a temperature rangingpreferably between about 0° C. and about 150° C.

Furthermore the etherified hydroxy groups may be converted into freehydroxy groups, for example, by treatment with pyridine hydrochloride orwith a strong acid such as HCl, HBr or Hl, or with a Lewis acid such asAlCl₃ or BBr₃. A compound of formula (I) wherein R₁ and/or R₂independently is a group ##STR14## alkyl wherein R' is as defined abovemay be converted into a compound of formula (I) wherein R₁ and/or R₂independently is a group ##STR15## wherein R' is as defined above byhydrolysis, e.g. acid hydrolysis, using, for example, HCl, HBr, Hl inwater, preferably in the presence of an organic solvent such as aceticacid or dioxane, operating at a temperature varying from roomtemperature to about 150° C.; the same reaction may be also carried oute.g. by treatment with lithium bromide in dimethylformamide at atemperature higher than 50° C.

A compound of formula (I) wherein R₁ and/or R₂ is independently a group##STR16## wherein R' is as defined above may be converted into anothercompound of formula (I) wherein R₁ and/or R₂ is independently a group offormula ##STR17## alkyl by conventional methods, for example by reactingan alkaline salt of the acid with a suitable alkyl halide in an inertsolvent, such as acetone, dioxane, dimethylformamide orhexamethylphosphorotriamide at a temperature ranging from 0° C. to about100° C.

Alternatively the esterification of a compound of formula (I) wherein R₁and/or R₂ is independently a group ##STR18## wherein R' is as definedabove, may be effected by converting the carboxylic acid into thecorresponding halocarbonyl, preferably chlorocarbonyl, derivate, byreaction, e.g., with the desired acid halide, for example oxalylchloride, thionyl chloride, PCl₃, PCl₅ or POCl₃, either in the absenceof solvents or in an inert organic solvent such as benzene, toluene,xylene, dioxane, dichloroethane, methylene chloride or tetrahydrofuran,at a temperature ranging preferably from about 0° C. to about 120° C.;and then by reacting the resulting halocarbonyl derivative with thesuitable alcohol of formula R"--OH, wherein R" is a C₁ -C₄ alkyl group,in an inert solvent such as benzene, toluene, xylene, dioxane,dichloroethane, methylene chloride or tetrahydrofuran, at temperaturesvarying between about 0° C. and about 120° C., preferably in thepresence of a base, such as, triethylamine or pyridine. A hydroxy or anamino group as substituents in a phenyl ring in a compound of formula(I) may be converted respectively into a C₂ -C₈ alkanoyloxy or C₂ -C₈alkanoylamino group using conventional methods well known in organicchemistry.

A nitro group as substituent in a phenyl ring in a compound of formula(I) may be converted into an amino group by treatment, for example, withstannous chloride in concentrated hydrochloric acid, using, ifnecessary, an organic cosolvent such as acetic acid, dioxane,tetrahydrofuran, at a temperature varying between room temperature andabout 100° C.

Also the optional salification of a compound of formula (I) as well asthe conversion of a salt into the free compound and the separation of amixture of isomers into the single isomers may be carried out byconventional methods.

For example the separation of a mixture of optical isomers into theindividual isomers may be carried out by salification with an opticallyactive base and subsequent fractional crystallization.

Thus, the separation of a mixture of geometric isomers may be carriedout, for example, by fractional crystallization.

The compounds of formula (II) wherein R₃ is different from hydroxy andbromine may be prepared, e.g., by reacting a compound of formula (IX)##STR19## wherein R₁ and R₂ are as defined above or a salt thereof, witha compound of formula (X) ##STR20## wherein R₃ is as defined above butis different from hydroxy and bromine and R₁₃ is preferably C₁ -C₄alkyl.

The reaction between a compound of formula (IX) and a compound offormula (X) may, for example, be carried out in the presence of an acidcondensing agent such as polyphosphoric acid (polyphosphoric acid meansa mixture of about equal weights of 99% H₃ PO₄ and P₂ O₅), sulphuricacid, methanesulphonic acid or p-toluenesulphonic acid, at a temperatureranging preferably between about 50° C. and 150° C.; the reaction may becarried out in an organic solvent such as, dimethylformamide,dimethylacetamide, acetic acid, formic acid, benzene, toluene, xylene,ethylene glycol monomethylether, dichloroethane, or in the absence of asolvent. Alternatively the compounds of formula (II) wherein R₃ isalkoxy or alkenyloxy may, for example, be prepared by reacting acompound of formula (XI) ##STR21## wherein R₁ and R₂ are as definedabove, with a suitable C₁ -C₄ alkyl or C₃ -C₄ alkenyl halide, preferablychloride, bromide or iodide, in a solvent such as acetone, dioxane,dimethylformamide in the presence of a basic agent such as sodiumhydride, sodium methoxide, sodium or potassium carbonate, at atemperature ranging from the room temperature to about 120° C.

The compounds of formula (II) wherein R₃ is halogen, e.g., bromine orchlorine, may be obtained, for example, by reacting a compound offormula (II) wherein R₃ is hydrogen with a suitable halosuccinimide,e.g. N-bromosuccinimide, or with SO₂ Cl₂, operating at a temperatureranging from 20° C. to about 100° C. in a solvent such as benzene orcarbon tetrachloride, respectively.

The compounds of formula (IV) may be prepared by reacting a compound offormula (XII) ##STR22## wherein Y is a radical capable of beingconverted to an anion Y.sup.(-) as defined above and R₁, R₂ and R₃ areas defined above, with P(Q)₃, where Q is as defined above, in a solventsuch as, benzene, toluene, xylene or acetonitrile at a temperaturevarying between room temperature and reflux temperature.

The compounds of formula (V) may be prepared for example by oxidizing acompound of formula (XIII) ##STR23## wherein R₁, R₂ and R₃ are asdefined above, for example, with dimethylsulfoxide in the presence ofdicyclohexylcaarbodiimide and phosphoric acid orpyridinium-trifluoroacetate (Moffat reaction) in a solvent such abenzene, toluene or dimethylsulfoxide at a temperature varying between0° C. and 50° C.

Alternatively the compounds of formula (V) may be prepared for example,by hydrolysing a compound of formula (XIV) ##STR24## wherein R₁, R₂ andR₃ are as defined above and R₁₄ represents halogen, in particularchlorine or bromine, or a C₁ -C₆ alkoxy group: the hydrolysis of acompound of formula (XIV) may be carried out, for example, by treatmentwith an aqueous mineral acid such as HCl, HBr, Hl, H₂ SO₄ preferably inthe presence of a solvent such as methanol, ethanol, acetone, dioxane,tetrahydrofuran at a temperature varying from the room temperature toabout 120° C. The compounds of formula (VIII) may be prepared, forexample, by reacting a compound of formula (II) with an aldehyde offormula (III), using the same experimental conditions as defined above.

The compounds of formula (XI) may be prepared, for example, byhydrolyzing a compound of formula (XV) ##STR25## wherein R₁ and R₂ areas defined above and R₁₅ represents formyl or a C₂ -C₈ alkanoyl group:the hydrolysis may be carried out, for example, by treatment with a basesuch as NaHCO₃, KHCO₃, Na₂ CO₃, K₂ CO₃, NaOH, KOH or with a mineral acidsuch as HCl, HBr, Hl, H₂ SO₄, H₃ PO₄, in aqueous medium or in thepresence of an organic cosolvent as dioxane, acetone, methanol, ethanol,tetrahydrofuran, dimethylformamide, at a temperature varying betweenroom temperature an the reflux temperature.

The compounds of formula (XII) wherein Y is halogen and R₃ is hydrogenmay, for example, be prepared by reacting a compound of formula (IX) ora salt thereof, with a compound of formula (XVI) ##STR26## wherein R₁₃is as defined above and Y represents a halogen atom, preferablychlorine, using the same experimental conditions as defined above forthe reaction between a compound of formula (IX) and a compound offormula (X).

The compounds of formula (XII) wherein R₃ is different from hydrogen,and Y is halogen, e.g., chlorine or bromine, may be prepared, forexample, from a compound of formula (II), wherein R₃ is different fromhydrogen, by reaction with a N-halo-succinimide, preferablyN-bromosuccinimide, in a solvent such as benzene or CCl₄ at atemperature varying between room temperature and the reflux temperature.Alternatively the compounds of formula (XII) wherein R₃ is chlorine orbromine may be prepared by reacting a compound of formula (XII) whereinR₃ is hydrogen with a suitable halogenating agent such aschlorosuccinimide or bromosuccinimide, SO₂ Cl₂ or pyridinium bromideperbromide, operating at a temperature ranging from 0° C. to 100° C. andusing, for example, as solvent CCl₄ or dichloroethane in the reactionwith SO₂ Cl₂ ; pyridine in the reaction with pyridinium bromideperbromide and benzene in the reaction with an halosuccinimide.

The compounds of formula (XIII) may be prepared, for example, byreacting a compound of formula (XII) wherein Y is a good leaving group,for example, Cl or Br, with potassium or sodium acetate indimethylformamide at a temperature varying between room temperature and100° C., so obtaining the correspondining acetoxy-derivative, which inturn is hydrolysed to the corresponding alcohol (XIII), for example, bytreatment with 37% HCl in dioxane at a temperature varying between roomtemperature and the reflux temperature.

The compounds of formula (XIV) may be prepared, for example, by reactinga compound of formula (IX) with a compound of formula (XVII) ##STR27##wherein R₃, R₁₃ and R₁₄ are as defined above and R₁₆ represents amino,C₁ -C₆ alkoxy or tri(C₁ -C₆)alkyl-silyloxy, by heating in an inertsolvent such as dioxane, toluene, xylene, dimethylformamide,dimethylacetamide or in the absence of a solvent at a temperaturevarying from about 50° C. to about 170° C., preferably from about 120°C. to about 150° C.

The compounds of formula (XV) may be prepared by reacting a compound offormula (IX) or a salt thereof with a compound of formula (XVIII)##STR28## wherein R₁₃ and R₁₅ are as defined above.

The reaction between a compound of formula (IX) and a compound offormula (XVIII) may, for example, be carried out in the presence of anacid condensing agent such as polyphosphoric acid (polyphosphoric acidmeans a mixture of about equal weights of 99% H₃ PO₄ and P₂ O₅),sulphuric acid, methanesulphonic acid or p-toluenesulphonic acid, at atemperature ranging preferably between about 50° C. and 150° C.; thereaction is preferably carried out in an organic solvent such asdimethylformamide, dimethylacetamide, benzene, toluene, xylene, ethyleneglycol monomethylether or dichloroethane, but it may be also carried outin the absence of a solvent.

The compounds of formula (III), (VI), (VII), (IX), (X), (XVI) and (XVII)are known compounds and may be prepared by conventional methods: in somecases they are commercially available products.

The compounds of the present invention are active on the gastroentericsystem, in particular they are endowed with anti-ulcerogenic and gastricanti-secretory activity and are therefore useful in therapy, for examplein the prevention and treatment of peptic, e.g. duodenal, gastric andesophageal, ulcers and to inhibit gastric acid secretion. The compoundsof the invention are also useful for reducing the undesiderablegastrointestinal side-effects resulting from systemic administration ofanti-inflammatory prostaglandin synthetase inhibitors and may be,therefore, used for this purpose in association with them. Theanti-ulcerogenic activity of the compounds of the invention is shown,e.g., by the fact that they are active in the test of the inhibition ofrestraint ulcers in rats, according to the method of Bonfils et al.,(Therapie, 1960, 5, 1096; Jap. J. Pharmac. 1945, 43, 5). SixSprague-Dawley male rats (100-120 g) fasted 24 hours were used for theexperiment: a square flexible small-mesh wire netting was used for theimmobilization and 4 hours after the immobilization the rats weresacrificed, their stomachs were removed and the lesions counted under adissecting microscope. The tested compounds were administered per os(p.o.) one hour before the immobilization. The following Table I shows,for example, the approximate ED₅₀ values of the anti-ulcerogenicactivity obtained in the above test in the rat after oral administrationfor two compounds of this invention:

                  TABLE I                                                         ______________________________________                                                           Antiulcerogenic                                            Compound           activity p.o.                                              ______________________________________                                        7-trans-[2-(3-pyridyl)-ethenyl]-                                                                 ED.sub.50 =  9 mg/kg                                       5H--thiazolo[3,2-a]pyrimidine-                                                5-one                                                                         2-chloro-7-trans-[2-(3-pyridyl)-                                                                 ED.sub.50 =10 mg/kg                                        ethenyl]-5H--thiazolo[3,2-a]py-                                               rimidine-5-one                                                                ______________________________________                                    

The compounds of the invention own also gastric antisecretory activityas shown, e.g., by the fact that they proved to be active, afterintraduodenal administration, in inhibiting the gastric secretion inrats according to the method of H. Shay et al. (Gastroenter., 1945, 43,5). Gastric antisecretory activity was evaluated in rats by the pylorusligature technique. Six Sprague-Dawley male rats (110-130 g) were usedfor each group. Twenty-four hours before the test, the rats weredeprived of food but their water supply was maintained. On the day ofthe operation, the pylorus was ligated under light ether anaesthesia.Each compound was injected intraduodenally (i.d.) at the time of theligature. Four hours after the ligature the rats were sacrificed, thestomach secretion was collected and centrifuged at 3500 r.p.m. for 10minutes, and the volume, less sediment, was determined.

The amount of the free hydrochloric acid in the gastric juice wasdetermined by titration against 0.01 N sodium hydroxide to pH 7.0.

One of the preferred compounds of this invention having gastricantisecretory activity is, for example, the compound6-methoxy-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,which has an approximate ED₅₀ value of 30 mg/kg in the above test in therat, after intraduodenal administration.

The compounds of this invention possess also anti-inflammatory activityas demonstrated e.g. by the fact that they are active, after oraladministration, in inhibiting: (A) the edema formation in the hind pawof rats in response to a subplantar injection of carrageenin, accordingto the method of C. A. Winter et al. (J. Pharmac. Exp. Therap. 1963,141, 369) and P. Lence (Arch. Int. Pharmacodyn., 1962, 136, 237), and(B) the Reversed Passive Arthus Reaction (RPAR) in rat paw, induced bythe interaction of antigen and antibody resulting in the formation ofprecipitating immune complex, followed by fixation of complement andaccumulation of polymorphonuclear leucocytes at a focal point (D. K.GEMMELL, J. COTTNEY and A. J. LEWIS, Agents and Actions 9/1 pag. 107,1979). The compounds of this invention are also endowed with analgesicactivity. The analgesic activity was assessed, for example, by means ofphenylquinone induced writhing test in mice according to Siegmund[Siegmund et al. Proc. Soc. Exper. Biol. Med., 95, 729 (1957)].

Therefore the compounds of the invention may be used in therapy to treatpains and inflammatory processes, such as for example, rheumatoidarthritis and osteoarthrosis. The following Tables II and III show, forexample, the approximate ED₂₅ values of the anti-inflammatory activityin the above tests in the rat after oral administration for somecompounds of this invention:

                  TABLE II                                                        ______________________________________                                                           Anti-inflammatory activity                                 Compound           Carrageenin induced oedema                                 ______________________________________                                        7-trans-[2-(3-pyridyl)-ethenyl]-                                                                 ED.sub.25 =  6 mg/kg                                       5H--thiazolo[3,2-a]pyrimidine-                                                5-one                                                                         2-chloro-7-trans-[2-(3-pyridyl)-                                                                 ED.sub.25 = 16 mg/kg                                       ethenyl]-5H--thiazolo[3,2-a]pyrim-                                            idine-5-one                                                                   6-methoxy-7-trans-[2-(3-pyridyl)-                                                                ED.sub.25 = 15 mg/kg                                       ethenyl]-5H--thiazolo[3,2-a]pyrim-                                            idine-5-one                                                                   ______________________________________                                    

                  TABLE III                                                       ______________________________________                                                           Anti-inflammatory activity                                 Compound           RPAR reaction                                              ______________________________________                                        6-methyl-7-trans-[2-(3-pyridyl)-                                                                 ED.sub.25 = 22 mg/g                                        ethenyl]-5H--thiazolo[3,2-a]pyrim-                                            idine-5-one                                                                   2-chloro-7-trans-[2-(3-pyridyl)-                                                                 ED.sub.25 = 25 mg/kg                                       ethenyl]-5H--thiazolo-8 3,2-:a]pyrim-                                         idine-5-one                                                                   ______________________________________                                    

With regard to the analgesic activity, one of the preferred compounds ofthis invention is, for example, the compound2-chloro-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,wich has an approximate ED₂₅ value of 25 mg/kg in thephenylquinone-induced writhing test in the rat, after oraladministration. Furthermore the compounds of this invention areeffective in the inhibiting the TXA₂ synthetase in vivo and may betherefore useful in therapy, for example, in the prevention andtreatment of all kinds of thrombosis, peripheral vasculopaties andcoronary artery diseases.

The activity on the TXA₂ synthetase was evaluated, e.g., in rat byadministering the compounds at a single oral dose of 10 mg/kg anddetermining the concentration of TXB₂ in the serum of the animals killedtwo hours after the administration of the drug.

As preferred example of compound having TXA₂ synthetase inhibitingactivity, the following can be mentioned:

6-methyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one

In view of their high therapeutic index, the compounds of the inventioncan be used safely in medicine. For example, the approximate acutetoxicity (LD₅₀) of the compounds7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one and2-chloro-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-onein the mouse determined by single administration of increasing doses andmeasured on the seventh day of treatment, is higher than 800 mg/kg peros. Analogous toxicity data have been found for other compounds of theinvention.

The compounds of the invention can be administered in a variety ofdosage forms, e.g. orally, in the form of tablets, capsules, sugar orfilm coated tablets, liquid solutions or suspensions, rectally, in theform of suppositories, parenterally, e.g. intramuscularly, or byintravenous injection or infusion.

The dosage depends on the age, weight, conditions of the patient andadministration route; for example the dosage adopted for oraladministration to adult humans ranges from about 50 to about 200 mg prodose, from 1 to 5 times daily.

The invention includes pharmaceutical compositions comprising a compoundof the invention in association with a pharmaceutically acceptableexcipient (which can be a carrier or diluent).

The pharmaceutical compositions containing the compounds of theinvention are usually prepared following conventional methods and areadministered in a pharmaceutically suitable form.

For example, the solid oral forms may contain, together with the activecompound, diluents, e.g., lactose, dextrose, saccharose, cellulose, cornstarch or potato starch; lubricants, e.g. silica, talc, stearic acid,magnesium or calcium stearate, and/or polyethylene glycols; bindingagents, e.g. starches, arabic gums, gelatin, methylcellulose,carboxymethyl cellulose or polyvinyl pyrrolidone; disaggregating agents,e.g. a starch, alginic acid, alginates or sodium starch glycolate;effervescing mixtures; dyestuffs; sweeteners; wetting agents, such aslecithin, polysorbates, laurylsulphates; and, in general, non-toxic andpharmacologically inactive substances used in pharmaceuticalformulations. Said pharmaceutical preparations may be manufactured inknown manner, for example, by means of mixing, granulating, tabletting,sugar-coating, or film-coating processes. The liquid dispersions fororal administration may be e.g. syrups, emulsions and suspensions.

The syrups may contain as carrier, for example, saccharose or saccharosewith glycerine and/or mannitol and/or sorbitol; in particular a syrup tobe administered to diabetic patients can contain as carriers onlyproducts not metabolizable to glucose, or metabolizable in very smallamount to glucose, for example sorbitol.

The suspensions and the emulsiony may contain as carrier, for example, anatural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose, or polyvinyl alcohol.

The suspensions or solutions for intramuscular injections may containtogether with the active compound a pharmaceutically acceptable carrier,e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propyleneglycol, and if desired, a suitable amount of lidocaine hydrochloride.The solutions for intravenous injections or infusions may contain ascarrier, for example, sterile water or preferably they may be in theform of sterile, aqueous, isotonic saline solutions.

The suppositories may contain together with the active compound apharmaceutically acceptable carrier, e.g. cocoa-butter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactant orlecithin.

The following examples illustrate but do not limit the invention.

EXAMPLE 1 2-amino-thiazole (3.06 g) was reacted with ethyl2-methylacetoacetate (6.4 g) in polyphosphoric acid (15.3 g: 7.1 g of P₂O₅ and 8.2 g of 99% H₃ PO₄) under stirring at 100° C. for two hours.After cooling, dilution with ice water and neutralization, theprecipitate was filtered, washed with water and crystallized fromisopropyl ether to give 6,7-dimethyl-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 112°-113° C. (5.04 g), which was reacted with3-pyridine-carboxaldehyde (5.99 g) in methanol (130 ml) in the presenceof sodium methoxide (4.55 g) under stirring at reflux temperature for 12hours. After cooling the precipitate was filtered and washed with wateruntil neutral: crystallization from methanol gave 3.2 g of6-methyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 192°-194° C., NMR (CDCl₃) δ ppm: 2.36 (s) (3H, CH₃), 6.97 (d) (H,C-2 proton), 7.38 (dd) (1H, C-5 pyridyl proton), 7.38 (d) (1H, β-ethenylproton), 7.91 (d) (1H, δ-ethenyl proton), 7.97 (d) (1H, C-3 proton),8.00 (m) (1H, C-4 pyridyl proton), 8.62 (dd) (1H, C-6 pyridyl proton),8.88 (d) (1H, C-2 pyridyl proton); J_(H).sbsb.α_(H).sbsb.β =16 Hz.

By proceeding analogously, using the suitable aldehydes, the followingcompounds were prepared:

6-methyl-7-trans-[2-(4-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 252°-253° C.;

6-methyl-7-trans-[2-(6-methyl-2-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 198°-199° C.;

6-methyl-7-trans-[2-(1-methyl-2-pyrrolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-7-trans-[2-(2-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 189°-190° C.;

6-methyl-7-trans-(2-phenyl-ethenyl)-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 173°-175° C.;

6-methyl-7-trans-[2-(4-chloro-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 223°-224° C.;

6-methyl-7-trans-[2-(2,6-dichloro-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 202°-204° C.;

2-cyano-6-methyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-7-trans-[2-(3-methyl-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-7-trans-[2-(4-methyl-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 190°-192° C.;

6-methyl-7-trans-[2-(2-methoxy-3-ethoxy-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;and

6-methyl-2-phenyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 274°-277° C.

EXAMPLE 2

By proceeding according to the example 1, using the suitable ethyl2-alkyl-acetoacetates, the following compounds were prepared:

6-ethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 176°-177° C.;

6-propyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 190°-191° C.;

6-ethyl-7-trans-[2-(4-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-propyl-7-trans-[2-(2-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-ethyl-7-trans-[2-(2-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;and

6-ethyl-7-trans-[2-(6-methyl-2-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one.

EXAMPLE 3

By proceeding according to example 1, using ethyl 2-chloro-acetoacetate,the following compounds were prepared:

6-chloro-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 235°-237° C.;

6-chloro-7-trans-(2-phenyl-ethenyl)-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 230°-232° C.;

6-chloro-7-trans-[2-(4-chloro-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 271°-272° C.; and

6-chloro-7-trans-[2-(2,6-dichloro-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one.

EXAMPLE 4

2-amino-thiazole (5 g) was reacted with ethyl 4-chloroacetoacetate (10.8g) in polyphosphoric acid (25 g) under stirring at 100° C. for 8 hours.

After cooling, dilution with ice water and neutralization, theprecipitate was filtered and washed with water: the obtained7-chloromethyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 136°-138° C.,(8.8 g), was reacted with triphenylphosphine (12.8 g) in acetonitrile(130 ml) under stirring at reflux temperature for 30 hours. Aftercooling the precipitate was filtered and washed with isopropyl ether togive(5H-thiazolo[3,2-a]pyrimidine-5-one-7-yl)-methyl-triphenylphosphoniumchloride, m.p. 295°-299° C., (20.6 g), which was added under stirring toa suspension of 50% NaH (2.61 g) in dimethylsulphoxide (300 ml) anddichloroethane (200 ml) and reacted with 3-pyridine-carboxaldehyde (7.15g) at room temperature for 6 hours. After evaporation of thedichloro-ethane in vacuo the solution was diluted with ice water and theprecipitate was filtered and washed with water: crystallization fromisopropyl alcohol gave 6.2 g of7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p.206°-207° C., NMR (DMSO d6) δ ppm: 6.41 (s) (1H, C-6 proton), 7.36 (d)(1H, β-ethenyl proton), 7.45 (dd) (1H, C-5 pyridyl proton), 7.58 (d)(1H, C-2 proton), 7.82 (d) (1H, α-ethenyl proton), 8.06 (d) (1H, C-3proton), 8.17 (dt) (1H, C-4 pyridyl proton), 8.60 (dd) (1H, C-6 pyridylproton), 8.91 (d) (1H, C-2 pyridyl proton); J_(H).sbsb.α_(H).sbsb.β =16Hz.

By proceeding analogously, using the suitable aldehydes, the followingcompounds were prepared:

7-trans-[2-(2-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p.231°-232° C.;

7-trans-[2-(4-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p.246°-247° C.;

7-trans-[2-(6-methyl-2-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 213°-216° C.;

7-trans-[2-(2-pyrrolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 209°-211° C.;

7-trans-[2-(1-methyl-2-pyrrolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 211°-212° C.;

7-trans-[2-(1-ethyl-2-pyrrolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

7-trans-(2-phenyl-ethenyl)-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p.198°-200° C.;

7-trans-[2-(3-chloro-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 230°-233° C.;

7-trans-[2-(4-chloro-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 208°-209° C.;

7-trans-[2-(2,6-dichloro-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 175°-177° C.;

7-trans-[2-(3-methoxy-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 185°-186° C.;

7-trans-[2-(3-hydroxy-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 226°-229° C.;

7-trans-[2-(4-hydroxy-3-iodo-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 250°-270° C. dec.;

7-trans-[2-(4-N,N-dimethylamino-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 233°-234° C.;

7-trans-[2-(2-nitro-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 280°-290° C. dec.;

7-trans-{2-[3-(3-N,N-dimethylamino)-propoxy-phenyl]-ethenyl}-5H-thiazolo[3,2-a]pyrimidine-5-one;

7-trans-[2-(4-methyl-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 214°-216° C.;

7-trans-[2-(3-methyl-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;and

7-trans-[2-(2-methoxy-3-ethoxy-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one.

EXAMPLE 5

2-amino-5-chloro-thiazole hydrochloride (8 g) was reacted withethyl-4-chloroacetoacetate (15.8 g) in polyphosphoric acid (40 g) understirring at 110° C. for 1 hour. After cooling, dilution with water andneutralization with 35% NaOH, the precipitate was filtered and washedwith water. Cristallization from isopropyl ether gave2-chloro-7-chloromethyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p.123°-125° C. (7.45 g), which was reacted with triphenylphosphine (9.42g) in acetonitrile (100 ml) under stirring at reflux temperature for 10hours. After cooling the precipitate was filtered and washed withacetonitrile to give(2-chloro-5H-thiazolo[3,2-a]pyrimidine-5-one-7-yl)-methyl-triphenylphosphoniumchloride, m.p. 300°-310° C. dec. (10 g) which was suspended indimethylsulfoxide (40 ml) and treated with potassium tert-butoxide (2.48g) dissolved in dimethylsulfoxide (40 ml) at room temperature understirring for 10 minutes. To the solution of the ylide so obtained 3-pyridine-carboxaldehyde (2.45 g) dissolved in dimethylsulfoxide (20 ml)was added and the reaction mixture was kept under stirring at roomtemperature for 15 minutes: after dilution with ice water andneutralization with NaH₂ PO₄ the precipitate was filtered andcrystallized from CH₂ Cl₂ -isopropyl alcohol to give 4.3 g of2-chloro-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 189°-190° C., NMR (CDCl₃) δ ppm: 6.24 (s) (1H, C-6 proton), 6.91(d) (1H, β-ethenyl proton), 7.30 (dd) (1H, C-5 pyridyl proton), 7.71 (d)(1H, α-ethenyl proton), 7.82 (s) (1H, C-3 proton), 7.87 (ddd) (1H, C-4pyridyl proton), 8.55 (dd) (1H, C-6 pyridyl proton), 8.77 (d) (1H, C-2pyridyl proton); J_(H).sbsb.α_(H).sbsb.β =16 Hz.

By proceeding analogously the following compounds were prepared:

2-chloro-7-trans-[2-(4-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

2-chloro-7-trans-[2-(1-methyl-2-pyrrolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-methyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 191°-193° C.;

2,3-dimethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 179°-180° C.;

3-trifluoromethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 224°-226° C.;

2-bromo-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 211°-213° C.;

3-tert.butyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

2-cyano-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 248°-250° C., NMR (DMSO d6) δ ppm: 6.40 (s) (1H, C-6 proton), 7.32(d) (1H, β-ethenyl proton), 7.44 (dd) (1H, C-5 pyridyl proton), 7.72 (d)(1H, α-ethenyl proton), 8.11 (ddd) (1H, C-4 pyridyl proton), 8.52 (m)(1H, C-6 pyridyl proton), 8.84 (dd) (1H, C-2 pyridyl proton), 9.00 (s)(1H, C-3 proton); J_(H).sbsb.α_(H).sbsb.β =16 Hz.

EXAMPLE 6

7-chloromethyl-3-phenyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p.194°-195° C. (7.8 g), prepared according to Example 5, was reacted withtriphenylphosphine (8 g) in acetonitrile (250 ml) under stirring at thereflux temperature for 24 hours. After cooling the solution wasconcentrated in vacuo to a small volume, diluted with isopropyl etherand the precipitate was filtered to give 11 g of[3-phenyl-5H-thiazolo[3,2-a]pyrimidine-5-one-7-yl]-methyl-triphenylphosphoniumchloride, which was suspended in dimethylsulfoxide (50 ml) and treatedwith potassium tert-butoxide (2.46 g) dissolved in dimethylsulfoxide (50ml) under stirring at room temperature. The solution of the ylide soobtained was reacted with 3-pyridine-carboxaldehyde (2.36 g) at roomtemperature for 60 minutes then the reaction mixture was diluted withice water and neutralized with NaH₂ PO₄.

The precipitate was filtered and washed with water: crystallization fromCH₂ Cl₂ -methanol gave 2.8 g of3-phenyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 270°-272° C., NMR (CDCl₃) δ ppm: 6.17 (s) (1H, C-6 proton), 6.70(s) (1H, C-2 proton), 6.97 (d) (1H, β-ethenyl proton), 7.34 (dd) (1H,C-5 pyridyl proton), 6.39 (s) (5H, phenyl protons), 7.77 (d) (1H,α-ethenyl proton), 7.87 (m) (1H, C-4 pyridyl proton), 8.54 (m) (1H, C-6pyridyl proton), 8.80 (dd) (1H, C-2 pyridyl proton);J_(H).sbsb.α_(H).sbsb.β =16 Hz.

By proceeding analogously the following compounds were prepared:

2-phenyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(4-fluoro-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 241°-243° C.;

3-(2-chloro-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(3-chloro-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(4-chloro-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 282°-283° C.;

3-(3-trifluoromethyl-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(2-methyl-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(3-methyl-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(4-methyl-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 254°-255° C.;

3-(2-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(3-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 209°-210° C.;

3-(4-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 241°-242° C.;

3-(2,4-dimethoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5-thiazolo[3,2-a]pyrimidine-5-one;

3-(3,4-dimethoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(3,4-ethylenedioxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 232°-236° C.;

3-(3,4-methylenedioxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(3,4-dihydroxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(4-hydroxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

2-methyl-3-phenyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 234°-237° C.;

2-ethyl-3-phenyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(4-biphenylyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 239°-240° C.;

3-(2-naphtyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 308°-310° C.;

3-(3-hydroxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

4-(4-acetoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(2-nitro-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 264°-266° C.;

3-(4-nitro-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 290°-293° C. (dec);

3-(2-amino-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(3-amino-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-(4-amino-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 282°-284° C. (dec); and

2,3-diphenyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 249°-250° C.

EXAMPLE 7

7-chloromethyl-3-(3-pyridyl)-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p.280°-290° C. dec. (5.30 g), prepared according to Example 6, was reactedwith triphenylphosphine (5 g) in acetonitrile (500 ml) under stirring atthe reflux temperature for 40 hours. After cooling the solution wasconcentrated in vacuo to a small volume, diluted with isopropyl etherand the precipitate was filtered to give 8 g of[3-(3-pyridyl)-5H-thiazolo[3,2-a]pyrimidine-5-one-7-yl]methyl-triphenylphosphoniumchloride, which was suspended in dimethylsulfoxide (100 ml) and treatedwith potassium tert-butoxide (1.66 g) dissolved in dimethylsulfoxide (50ml) under stirring at room temperature. The solution of the ylide soobtained was reacted with 3-pyridine-carboxaldehyde (1.74 g) at roomtemperature for 30 minutes then the reaction mixture was diluted withice water and neutralized with NaH₂ PO₄.

The precipitate was filtered and washed with water: crystallization fromCH₂ Cl₂ -methanol gave 2.8 g of3-(3-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 270°-272° C. NMR (CF₃ COOD+CDCl₃) δ ppm: 6.82 (s) (1H, C-6 proton),7.51 (d) (1H, β-ethenyl proton), 7.76 (s) (1H, C-2 proton), 7.96 (d)(1H, α-ethenyl proton), 8.01-8.36 (m) (2H, C-5 pyridyl protons),8.70-9.00 (m) (4H, C-4 and C-6 pyridyl protons), 9.11 (bs) (2H, C-2pyridyl protons); J_(H).sbsb.α_(H).sbsb.β =16 Hz.

By proceeding analogously the following compounds were prepared:

7-trans-[2-(3-pyridyl)-ethenyl]-3-(2-thienyl)-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 121°-125° C.;

3-(2-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;and

3-(4-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one.

EXAMPLE 8

2-amino-5-chloro-thiazole hydrochloride (8 g) was reacted withethyl-4-chloroacetoacetate (15.8 g) in polyphosphoric acid (40 g) understirring at 110° C. for 1 hour. After cooling, dilution with water andneutralization with 35% NaOH, the precipitate was filtered and washedwith water. Crystallization from isopropyl ether gave2-chloro-7-chloromethyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p.123°-125° C. (7.45 g), which was reacted with triphenylphosphine (9.42g) in acetonitrile (100 ml) under stirring at reflux temperature for 10hours. After cooling the precipitate was filtered and washed withacetonitrile to give(2-chloro-5H-thiazolo[3,2-a]pyrimidine-5-one-7-yl)-methyl-triphenylphosphoniumchloride, m.p. 300°-310° C. dec. (10 g) which was suspended indimethylsulfoxide (40 ml) and treated with potassium tert-butoxide (2.48g) dissolved in dimethylsulfoxide (40 ml) at room temperature understirring for 10 minutes. To the solution of the ylide so obtained 5-formyl-2-methyl-thiazole (3.1 g) dissolved in dimethylsulfoxide (20 ml)was added and the reaction mixture was kept under stirring at roomtemperature for 15 minutes: after dilution with ice water andneutralization with NaH₂ PO₄ the precipitate was filtered andcrystallized from CH₂ Cl₂ -methanol to give 3.4 g of2-chloro-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 224°-226° C., NMR (CDCl₃) δ ppm: 2.97 (s) (3H, --CH₃), 6.61 (s)(1H, C-6 proton), 6.78 (d) (1H, β-ethenyl proton), 7.82 (d) (1H,α-ethenyl proton), 7.88 (s) (1H, C-3 proton), 8.02 (s) (1H, C-4thiazolyl proton); J_(H).sbsb.α_(H).sbsb.β =16 Hz.

By proceeding analogously, starting from suitable 2-amino-thiazoles, thefollowing compounds were prepared:

7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 245°-248° C.;

2-cyano-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

2,3-dimethyl-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

2,3-diphenyl-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-3-phenyl-5H-thiazolo[3,2-a]pyrimidine-5-one;

7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-3-trifluoromethyl-5H-thiazolo[3,2-a]pyrimidine-5-one;and

7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-3-(3-pyridyl)-5H-thiazolo[3,2-a]pyrimidine-5-one.

EXAMPLE 9

7-chloromethyl-5H-thiazolo[3,2-a]pyrimidine-5-one (10 g), preparedaccording to Example 4, was dissolved in dimethylformamide (200 ml) andreacted with anhydrous potassium acetate (10 g) under stirring at roomtemperature for 20 hours.

After dilution with ice water the precipitate was filtered and washedwith water: crystallization from methanol gave7-acetoxymethyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 144°-145° C.,(7.5 g), which was hydrolysed by treatment with 37% HCl (50 ml) indioxane (100 ml) under stirring at room temperature for 1 hour.

The reaction mixture was diluted with acetone and the precipitate wasfiltered and then treated with aqueous Na₂ HPO₄ : filtration andwashings with water until neutral gave7-hydroxymethyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 189°-191° C.,(4.8 g), which was reacted with dicyclohexylcarbodiimide (12.6 g) inbenzene (80 ml) and dimethylsulphoxide (36 ml) in the presence oftrifluoroacetic acid (0.9 ml) and pyridine (1.53 ml) under stirring atroom temperature for 24 hours. After treatment with oxalic acidbihydrate (2.8 g) at room temperature, the precipitate ofdicyclohexylurea was filtered off and the organic solution wasconcentrated in vacuo to dryness: the residue was purified over a SiO₂column using chloroform-ethyl acetate 8:2 as eluent. Crystallizationfrom ethyl acetate gave 7-formyl-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 184°-186° C., (1.3 g), which was reacted withtriphenylphosphonium-benzyl chloride (1.87 g) under treatment with 50%NaH (0.274 g) in dimethylsulphoxide (6 ml) and dichloroethane (4 ml) atroom temperature for 16 hours. After evaporation of solvent in vacuo,the solution was diluted with ice water and the precipitate was filteredand washed with water: crystallization from isopropyl ether gave 1.2 gof 7-trans-(2-phenyl-ethenyl)-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p.198°-200° C., NMR (DMSO d6) δ ppm: 6.40 (s) (1H, C-6 proton), 7.22 (d)(1H, β-ethenyl proton), 7.3-7.8 (m) (5H, phenyl protons), 7.54 (d) (1H,C-2-proton), 7.80 (d) (1H, α-ethenyl proton), 8.04 (d) (1H, C-3 proton);J_(H).sbsb.α_(H).sbsb.β =16 Hz.

EXAMPLE 10

2-amino-4,5-dimethyl-thiazole (2 g) was reacted with ethyl3-amino-4,4-diethoxy-2-methyl-crotonate (5.4 g) in dimethylacetamide (15ml) under stirring at 140° C. for 15 hours. After cooling the reactionmixture was diluted with ice water and extracted with ethyl acetate: theorganic phase was washed with N/10 HCl and water and then decolorizedwith charcoal.

After evaporation in vacuo to dryness, the residue was purified over aflash column using hexane-ethyl acetate 3:2 as eluent, so obtaining 0.9g of7-diethoxymethyl-2,3,6-trimethyl-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 84°-85° C., which was dissolved in dioxane (10 ml) and treated with5% HCl (15 ml) under stirring at 50° C. for 30 minutes. After coolingthe solution was neutralized with 10% NaOH, diluted with ice water andextracted with ethyl acetate: the organic solution was evaporated todryness in vacuo and the residue was crystallized from hexane to give0.6 g of 7-formyl-2,3-6-trimethyl-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 170°-173° C., which was reacted at room temperature for 1 hour withthe ylide obtained by treatment of(3-pyridyl)-methyl-triphenylphosphonium chloride (1.05 g) with potassiumtert-butoxide (0.3 g) in dimethylsulfoxide (30 ml).

The reaction mixture was diluted with ice water containing NaH₂ PO₄ thenit was extracted with ethyl acetate: the organic solution was evaporatedin vacuo to dryness and the residue was crystallized from isopropylalcohol-hexane to give 0.25 g of2,3,6-trimethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 193°-195° C., NMR (CDCl₃) δ ppm: 2.22 (s) (3H, CH₃), 2.24 (s) (3H,CH₃), 2.70 (s) (3H, CH₃), 7.22 (d) (1H, β-ethenyl proton), 7.28 (ddd)(1H, C-5 pyridyl proton), 7.74 (d) (1H, α-ethenyl proton), 7.86 (ddd)(1H, C-4 pyridyl proton), 8.49 (d) (1H, C-6-pyridyl proton), 8.75 (dd)(1H, C-2 pyridyl proton); J_(H).sbsb.α_(H).sbsb.β =16 Hz.

By proceeding analogously the following compounds were prepared:

2-chloro-6-methyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,NMR (CDCl₃) δ ppm: 2.28 (s) (3H, CH₃), 6.94 (d) (1H, β-ethenyl proton),7.19 (dd) (1H, C-5 pyridyl proton), 7.80 (s) (1H, C-3 proton), 7.75 (d)(1H, α-ethenyl proton), 7.78 (bd) (1H, C-4 pyridyl proton), 8.56 (m)(1H, C-6 pyridyl proton), 8.77 (d) (1H, C-2 pyridyl proton); J_(H)αHβ=16 Hz;

3,6-dimethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 211°-214° C.;

NMR (CDCl₃) δ p.p.m.: 2.24 (s) (3H, C-6 methyl), 2.80 (d) (3H, C-3methyl), 6.30 (q) (1H, C-2 proton), 7.24 (d) (1H, β-ethenyl proton),7.29 (dd) (1H, C-5 pyridyl proton), 7.78 (d) (1H, α-ethenyl proton),7.85 (ddd) (1H, C-4 pyridyl proton), 8.51 (dd) (1H, C-6 pyridyl proton),8.77 (d) (1H, C-2 pyridyl proton); J_(H)αHβ =16 Hz.

EXAMPLE 11

2-amino-thiazole (10 g) was reacted with ethyl 2-acetoxy-acetoacetate(37.5 g) in dimethylacetamide (375 ml) containing polyphosphoric acid(71.5 g: 42.5 g of P₂ O₅ and 29 g of H₃ PO₄) under stirring at 100° C.for 24 hours. After cooling, dilution with ice water and neutralizationwith Na₂ HPO₄, the precipitate was extracted with ethyl acetate: theorganic solution was evaporated in vacuo to dryness and the residue waspurified over a SiO₂ column using CHCl₃ as eluent.

Crystallization from isopropyl ether gave 8 g of6-acetoxy-7-methyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 118°-119°C., which was hydrolyzed by treatment with NaHCO₃ (16 g) in methanol (80ml) under stirring at 60° C. for 4 hours. After cooling the solution wasevaporated in vacuo to a small volume and the residue was dissolved inethyl acetate and then repeatedly extracted with aqueous NaOH.

The aqueous phase was neutralized with 37% HCl and the precipitate wasextracted with chloroform: the organic solution was evaporated in vacuoto dryness. Crystallization from ethyl acetate gave 5.3 g of6-hydroxy-7-methyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 225°-227°C., which was dissolved in dimethylformamide (50 ml) and reacted withmethyl iodide (8.3 g) in the presence of anhydrous K₂ CO₃ (8.1 g) understirring at room temperature for 16 hours. The reaction mixture wasdiluted with ice water and extracted with ethyl acetate then the organicsolution was treated with gaseous HCl. The precipitate was filtered andwashed with ethyl acetate:6-methoxy-7-methyl-5H-thiazolo[3,2-a]pyrimidine-5-one hydrochloride,m.p. 185°-195° C. dec. (4.7 g) was obtained, which was reacted with3-pyridyl-carboxaldehyde (5.4 g) in methanol (140 ml) in the presence ofsodum methoxide (3.3 g) under stirring at reflux temperature for 24hours. After concentration in vacuo to a small volume and dilution withisopropyl ether, the precipitate was filtered and washed with isopropylether and then with water. Crystallization from 50% ethanol gave 3.2 gof6-methoxy-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 186°-187° C., NMR (CDCl₃) δ ppm: 4.02 (s) (3H, --OCH₃), 6.96 (d)(1H, C-2 proton), 7.32 (dd) (1H, C-5 pyridyl proton), 7.50 (d) (1H,β-ethenyl proton), 7.80 (d) (1H, α-ethenyl proton), 7.89 (d) (1H, C-3proton), 7.96 (dt) (1H, C-4 pyridyl proton), 8.53 (dd) (1H, C-6 pyridylproton), 8.81 (bs) (1H, C-2 pyridyl proton); J_(H).sbsb.α_(H).sbsb.β =16Hz.

By proceeding analogoulsy, using suitable aryl or heteroaryl aldehydes,the following compounds were prepared:

6-methoxy-7-trans-[2-(2-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methoxy-7-trans-[2-(6-methyl-2-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-hydroxy-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-ethoxy-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 163°-165° C.;

6-methoxy-7-trans-[2-(4-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methoxy-7-trans-(2-phenyl-ethenyl)-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methoxy-7-trans-[2-(2,6-dichloro-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;and

6-propoxy-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one.

EXAMPLE 12

2-amino-5-chloro-thiazole hydrochloride (10 g) was reacted with ethyl2-acetoxy-acetoacetate (22 g) in dimethylacetamide (400 ml) containingpolyphosphoric acid (71 g: 29 g of H₃ PO₄ and 42 g of P₂ O₅) understirring at 100° C. for 6 hours. After cooling, dilution with ice waterand neutralization with 37% NaOH, the precipitate was extracted withethyl acetate and the organic solution was evaporated in vacuo todryness. The residue was hydrolyzed by treatment with 35% HCl (50 ml) indioxane (100 ml) at reflux temperature for 2 hours: after cooling thereaction mixture was diluted with ice water and neutralized with 37%NaOH and the precipitate was extracted with ethyl acetate. The organicsolution was evaporated in vacuo to dryness and the residue wascrystallized from methanol to give 5.85 g of2-chloro-6-hydroxy-7-methyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p.214°-217° C., which was dissolved in dimethylformamide (100 ml) andreacted with methyl iodide (15.4 g) in the presence of anhydrous K₂ CO₃(15 g) under stirring at 60° C. for 3 hours. After cooling the reactionmixture was diluted in ice water and neutralized with NaH₂ PO₄ : theprecipitate was filtered and the aqueous phase was extracted with ethylacetate for the complete recovering of the product. On the whole it wasobtained 5.1 g of2-chloro-6-methoxy-7-methyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p.138°-141° C., which was reacted with N-bromosuccinimide (17 g, addedportionwise) in benzene (150 ml) at the reflux temperature for 40 hours.After cooling the reaction mixture was diluted with ethyl acetate andtreated with aqueous NaHCO₃ and then with water: the separated organicsolution was evaporated in vacuo to dryness and the residue wascrystallized from ethyl acetate to give 2.8 g of7-bromomethyl-2-chloro-6-methoxy-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 160°-162° C., which was reacted with triphenylphosphine (2.6 g) inacetonitrile (50 ml ) at the reflux temperature for 3 hours. Aftercooling and evaporation in vacuo of the solvent, the residue waspurified with ethyl acetate to give 3.8 g of(2-chloro-6-methoxy-5H-thiazolo[3,2-a]pyrimidine-5-one-7-yl)-methyl-triphenylphosphoniumbromide, which was suspended in dimethylsulfoxide (45 ml) and treatedwith potassium tert-butoxide (0.75 g) dissolved in dimethylsulfoxide (20ml) at room temperature under stirring for 10 minutes.

The solution of the ylide so obtained was reacted with3-pyridine-carboxaldehyde (0.94 g) at room temperature for 1 hour. Thereaction mixture was diluted with ice water, neutralized with NaH₂ PO₄and the precipitate was filtered: crystallization from ethanol gave 0.96g of2-chloro-6-methoxy-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 205°-207° C., NMR (CDCl₃ --CF₃ COOD) δ ppm: 3.99 (s) (3H, OCH₃),7.69 (d) (1H, β-ethenyl proton), 7.93 (d) (1H, α-ethenyl proton), 7.99(s) (1H, C-3 proton), 8.08 (m) (1H, C-5 pyridyl proton), 8.75 (m) (2H,C-4 and C-6 pyridyl protons), 9.02 (bs) (1H, C-2 pyridyl proton);J_(H).sbsb.α_(H).sbsb.β =16 Hz.

By proceeding analogously the following compounds were prepared:

6-methoxy-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

2-chloro-6-ethoxy-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazol[3,2-a]pyrimidine-5-one;

6-methoxy-7-trans-[2-(1-methyl-2-pyrrolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methoxy-3-(2-thienyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

2-chloro-6-methoxy-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 225°-227° C.,

NMR (CDCl₃) δ ppm: 2.71 (s) (3H, --CH₃), 3.98 (s) (3H, OCH₃), 7.02 (d)(1H, β-ethenyl proton), 7.68 (s) (1H, C-4 thiazolyl proton), 7.76 (s)(1H, C-3 proton), 7.81 (d) (1H, α-ethenyl proton);J_(H).sbsb.α_(H).sbsb.β =16 Hz.

6-methoxy-3-trifluoromethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methoxy-3-(3-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methoxy-3-(2-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methoxy-3-(4-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methoxy-3-(4-biphenylyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-methyl-6-methoxy-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

2,3-dimethyl-6-methoxy-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methoxy-3-(3-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methoxy-3-(4-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methoxy-3-(4-chloro-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methoxy-3-(4-methyl-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;and

6-methoxy-3-phenyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one.

EXAMPLE 13

By proceeding according to Example 12, using ethyl2-methyl-acetoacetate, the following compounds were prepared:

6-methyl-3-trifluoromethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-3-(3-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-3-(2-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-3-(4-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-3-(4-biphenylyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

2-chloro-6-methyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-3-phenyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-3-(4-chloro-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-3-(4-methyl-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-3-(4-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl[-5H-thiazolo[3,2-a]pyrimidine-5-one;and

6-methyl-3-(2-thienyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one.

EXAMPLE 14

2-chloro-7-chloromethyl-5H-thiazolo[3,2-a]pyrimidine-5-one, (6.07 g),prepared according to Example 5, was reacted with sulfuryl chloride (3.8g) in dichloroethane (150 ml) under stirring at room temperature for 4hours. The reaction mixture was treated with 5% aqueous NaHCO₃ solutionthen the organic phase was separated and evaporated in vacuo to dryness.Crystallization from methanol gave 5.6 g of2,6-dichloro-7-chloromethyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p.117°-119° C. dec., which was reacted with triphenylphosphine (5.95 g) inacetonitrile (115 ml) at the reflux temperature for 20 hours. Thesolution was evaporated in vacuo to dryness and the residue was purifiedwith isopropyl ether to give 10.4 g of[2,6-dichloro-5H-thiazolo[3,2-a]pyrimidine-5-one-7-yl]-methyl-triphenylphosphoniumchloride, which was suspended in dimethylsulfoxide (50 ml) and treatedwith potassium tert-butoxide (2.41 g) dissolved in dimethylsulfoxide (45ml) at room temperature.

The solution of the ylide so obtained was reacted with3-pyridine-carboxaldehyde (2.36 g) at room temperature for 20 hours. Thereaction mixture was diluted with ice water, neutralized with NaH₂ PO₄and the precipitate was filtered: crystallization from methanol gave3.45 g of2,6-dichloro-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 242°-243° C.; NMR (CDCl₃) δ ppm: 7.33 (dd) (1H, C-5 pyridylproton), 7.51 (d) (1H, β-ethenyl proton), 7.83 (s) (1H, C-3 proton),7.88 (d) (1H, α-ethenyl proton), 7.91 (dt) (1H, C-4 pyridyl proton),8.58 (bd) (1H, C-6 pyridyl proton), 8.80 (bs) (1H, C-2 pyridyl proton);J_(H).sbsb.α_(H).sbsb.β =16 Uz.

By proceeding analogously the following compounds were prepared:

6-chloro-3-methyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 219°-220° C.;

6-chloro-2,3-dimethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 226°-228° C.;

6-chloro-3-phenyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 203°-204° C.;

6-chloro-3-(4-chloro-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 278°-280° C.;

6-chloro-3-(4-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 264°-265° C.;

6-chloro-3-(4-fluoro-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 268°-269° C.;

6-chloro-3-(4-methyl-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 258°-259° C.;

6-chloro-3-(3-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(2-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(2-thienyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-tert.butyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-trifluoromethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 247°-249° C.;

6-chloro-3-(3,4-ethylenedioxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(3,4-dimethoxy-phenyl)7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(2,4-dimethoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-2-methyl-3-phenyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 229°-232° C.;

6-chloro-2-cyano-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(3-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 274°-275° C.;

6-chloro-3-(2-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(4-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(4-biphenylyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(2-naphthyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(2-nitro-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(2-amino-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(3-amino-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(4-amino-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 230°-233° C.;

2,6-dichloro-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-methyl-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-2,3-dimethyl-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-3-phenyl-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 190°-192° C.;

6-chloro-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-3-trifluoromethyl-5H-thiazolo[3,2-a]pyrimidine-5-one;and

6-chloro-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-3-(3-pyridyl)-5H-thiazolo[3,2-a]pyrimidine-5-one.

EXAMPLE 15

4-carbethoxymethyl-2-amino-thiazole (14 g) was reacted with ethyl4-chloro-acetoacetate (19.3 g) in polyphosphoric acid (70 g) understirring at 100° C. for 2.5 hours. After cooling, dilution with icewater and neutralization, the precipitate was filtered and washed withwater: the obtained3-carbethoxymethyl-7-chloromethyl-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 94°-95° C. (19 g) was reacted with triphenyl-phosphine (19.1 g) inacetonitrile (100 ml) under stirring at reflux temperature for 20 hours.After cooling the precipitate was filtered and washed with isopropylether to give(3-carbethoxymethyl-5H-thiazolo[3,2-a]pyrimidine-5-one-7-yl)-methyl-triphenylphosphoniumchloride, m.p. 295° C. dec. (15 g), which was added under stirring to asuspension of 75% NaH (1.31 g) in dichloroethane (100 ml) anddimethylsulphoxide (100 ml) and reacted with 3-pyridine-carboxaldehyde(5.76 g) at 25° C. for 6 hours.

The reaction mixture was diluted with ice water, neutralized to pH 6with NaH₂ PO₄ and extracted with dichloroethane: after evaporation invacuo to dryness the residue was crystallized from methanol to give7-trans-[2-(3-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid, ethyl ester, m.p. 185°-187° C. (5.35 g), which was heated with 37%HCl (60 ml) and acetic acid (60 ml) at reflux temperature for 1 hour;after cooling, dilution with ice water and neutralization to pH 6 with35% NaOH, the precipitate was filtered and crystallized fromdimethylformamide-water to give 3.3 g of7-trans-[2-(3-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid, m.p. 300° C. dec.

NMR (CF₃ COOD) δppm: 4.61 (bs) (2H, CH₂ COOH), 7.07 (s) (1H, C-6proton), 7.66 (d) (1H, β-ethenyl proton), 7.68 (s) (1H, C-2 proton),8.06 (d) (1H, α-ethenyl proton), 8.40 (dd) (1H, C-5 pyridyl proton),9.09 (m) (2H, C-4 and C-6 pyridyl protons), 9.37 (bs) (1H, C-2 pyridylproton); J_(H).sbsb.α_(H).sbsb.β =16 Hz.

By proceeding analogously, using the suitable aldehydes, the followingcompounds were prepared:

7-trans-[2-(2-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

7-trans-[2-(4-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

7-trans-[2-(6-methyl-2-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

7-trans-[2-(1-methyl-2-pyrrolyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid, m.p. 252°-255° C.;

7-trans-[2-(4-methoxy-phenyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

7-trans-[2-(4-chloro-phenyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

7-trans-[2-(2,6-dichloro-phenyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid; and

7-trans-[2-(2,4-dichloro-phenyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid.

EXAMPLE 16

By proceeding according to Example 9, starting from suitable6-substituted-5H-thiazolo[3,2-a]pyrimidine-5-ones, the followingcompounds were prepared:

6-methyl-7-trans-[2-(3-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

6-chloro-7-trans-[2-(2-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

6-chloro-7-trans-[2-(4-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

6-chloro-7-trans-[2-(6-methyl-2-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

6-chloro-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

6-chloro-7-trans-[2-(1-methyl-2-pyrrolyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

6-methyl-7-trans-[2-(4-methoxy-phenyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

6-methyl-7-trans-[2-(4-chloro-phenyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

6-methyl-7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

6-chloro-7-trans-[2-(2,6-dichloro-phenyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

6-chloro-7-trans-[2-(3-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid, m.p. 320°-330° C. dec.,

NMR (CDCl₃ --CF₃ COOD) δp.p.m.: 4.30 (s) (2H, --CH₂ COO--), 7.11 (s)(1H, C-2 proton), 7.73 (d) (1H, β-ethenyl proton), 7.98 (d) (1H,α-ethenyl proton), 8.09 (m) (1H, C-5 pyridyl proton), 8.80 (m) (2H, C-4and C-6 pyridyl protons), 9.08 (bs) (1H, C-2 pyridyl proton); J_(H)αHβ=16 Hz;6-chloro-7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid, m.p. 301°-303° C., and6-chloro-7-trans-[2-(4-methoxy-phenyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid.

EXAMPLE 17

7-methyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 127°-129° C., (4 g),prepared according to Example 1 using ethyl acetoacetate, dissolved inbenzene (100 ml) was reacted with N-bromo-succinimide (4.7 g) understirring at room temperature for 1 hour. The precipitate was dissolvedby adding chloroform and the solution was washed with water: evaporationin vacuo to dryness and crystallization of the residue from methanolgave 6-bromo-7-methyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 233°-234°C. (5.1 g), which was reacted with 3-pyridine-carboxaldehyde (3.4 g) inmethanol (190 ml) in the presence of sodium methoxide (2.2 g) understirring at the reflux temperature for 2 hours. After cooling theprecipitate was filtered and washed with water until neutral:crystallization from CH₂ Cl₂ -methanol gave 5.18 g of6-bromo-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 208°-209° C., NMR (CDCl₃) δppm: 6.99 (d) (1H, C-2 proton), 7.33(dd) (1H, C-5 pyridyl proton), 7.59 (d) (1H, β-ethenyl proton), 7.95 (d)(1H, α-ethenyl proton), 7.96 (d) (1H, C-3 proton), 7.98 (m) (1H, C-4pyridyl proton), 8.58 (bd) (1H, C-6 pyridyl proton), 8.82 (bs) (1H, C-2pyridyl proton); J_(H).sbsb.α_(H).sbsb.β =16 Hz.

By proceeding analogously the following compounds were prepared:

6-bromo-7-trans-[2-(2-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-bromo-7-trans-[2-(4-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;and

6-bromo-trans-[2-(6-methyl-2-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one.

EXAMPLE 18

7-trans-[2-(2-nitro-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one(10 g), obtained according to Example 4, was reacted with SnCl₂.2H₂ O(74 g) in 37% HCl (45 ml) and acetic acid (135 ml) under stirring at 60°C. for 24 hours. After cooling the precipitate was filtered, washed withwater until neutral and then suspended under stirring in 2.5% aqueousNaHCO₃ solution (300 ml). The precipitate was filtered and washed withwater until neutral: after purification with hot chloroform 5.5 g of7-trans-[2-(2-amino-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 246°-248° C., were obtained; NMR (CDCl₃ -DMSO d6-CF₃ COOD) δppm:6.62 (s) (1H, C-6 proton), 7.10 (d) (1H, β-ethenyl proton), 7.48 (d)(1H, C-2 proton), 7.55 (m) (3H, C-3, C-4 and C-5 phenyl protons), 7.88(m) (1H, C-6 phenyl proton), 8.16 (d) (1H, α-ethenyl proton), 8.18 (d)(1H, C-3 proton); J_(H).sbsb.α_(H).sbsb.β =16 Hz.

By proceeding analogously the following compounds were prepared:

3-(4-amino-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 282°-284° C. (dec);

3-(3-amino-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one.

EXAMPLE 19

7-trans-[2-(4-hydroxy-3-iodo-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one(1.4 g), prepared according to Example 4, was reacted with aceticanhydride (2.8 ml) in pyridine (5.6 ml) and dimethylacetamide (30 ml)under stirring at room temperature for 2 hours. After dilution with icewater the precipitate was filtered and washed with water until neutral:crystallization from dioxane gave 1.2 g of7-trans-[2-(4-acetoxy-3-iodo-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 272°-275° C., NMR (CDCl₃ --CF₃ COOD) δppm: 2.52 (s) (3H, --OCOCH₃),6.91 (s) (1H, C-6 proton), 7.03 (d) (1H, β-ethenyl proton), 7.22 (d)(1H, C-5 phenyl proton), 7.66 (d) (1H, α-ethenyl proton), 7.67 (d) (1H,C-2 proton), 7.67 (dd) (1H, C-6 phenyl proton), 8.13 (d) (1H, C-2 phenylproton), 8.37 (d) (1H, C-3 proton); H_(H)αHβ =16 Hz.

By proceeding analogously, the following compounds were prepared:

7-trans-[2-(2-N-acetylamino-phenyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 240°-242° C.;

3-(4-N-acetylamino-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 278°-280° C. (dec);

3-(3-N-acetylamino-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;and

3-(2-N-acetylamino-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one.

EXAMPLE 20

Trimethyl-sulphoxonium iodide (10.4 g) was reacted with 50% sodiumhydride (2.25 g) in dimethylformamide (50 ml) under stirring at roomtemperature for 1 hour, then a solution of7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one (6 g)in dimethylformamide (50 ml) was added.

The mixture was allowed to react under stirring at room temperature for20 hours, then it was diluted with ice water, neutralized with NaH₂ PO₄and extracted with chloroform. After evaporation in vacuo the cruderesidue was purified over a SiO₂ column using ethyl acetate as eluent:crystallization from ethyl acetate gave 2.35 g of7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 115°-117° C., NMR (CDCl₃) δppm: 1.50 (m) (1H, ##STR29## 1.89 (m)and 2.16 (m) ##STR30## 2.68 ##STR31## 6.28 (s) (1H, C-6 proton), 7.02(d) (1H, C-2 proton), 7.1-7.5 (m) (2H, C-4 and C-5 pyridyl protons),8.00 (d) (1H, C-3 proton), 8.5 (m) (2H, C-2 and C-6 pyridyl protons).

By proceeding analogously the following compounds were prepared:

6-methyl-7-trans-[2-(4-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 151°-152° C.;

6-ethyl-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

2-phenyl-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-7-trans-[2-(4-methyl-phenyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 153°-155° C.;

6-methyl-7-trans-[2-(2-methoxy-3-ethoxy-phenyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

7-trans-[2-(1-methyl-2-pyrrolyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3-methyl-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

3,6-dimethyl-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

2-chloro-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

7-trans-[2-(3-pyridyl)-cyclopropyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

7-trans-(2-phenyl-cyclopropyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

6-chloro-7-trans-[2-(3-pyridyl)-cyclopropyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

6-methyl-7-trans-[2-(3-pyridyl)-cyclopropyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

2,3,6-trimethyl-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 120° C. dec;

6-chloro-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 159°-161° C.;

6-chloro-3-phenyl-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;m.p. 136°-138° C.;

6-chloro-7-trans-[2-(2-methyl-5-thiazolyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 174°-175° C.;

6-methyl-2-phenyl-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 210°-213° C.;

6-methoxy-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 92°-95° C.;

2-chloro-6-methoxy-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-7-trans-[2-(2-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-methyl-7-trans-[2-(6-methyl-2-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-7-trans-[2-(3-pyridyl)-cyclopropyl]-3-trifluoromethyl-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-7-trans-[2-(3-pyridyl)-cyclopropyl]-3-(2-thienyl)-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(3-pyridyl)-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(2-pyridyl)-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(4-pyridyl)-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(4-biphenylyl)-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-phenyl-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(4-chloro-phenyl)-7-trans-[2-(3-pyridyl)cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;

6-chloro-3-(4-methyl-phenyl)-7-trans-[2-(3-pyridyl)cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;and

6-chloro-3-(4-methoxy-phenyl)-7-trans-[2-(3-pyridyl)cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one.

EXAMPLE 21

7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid (1.2 g) was reacted with thionyl chloride (0.6 ml) in dioxane (12ml) at reflux temperature for 2 hours, then the mixture was evaporatedto dryness in vacuo. The residue was reacted with excess of ethanol at50° C. for 30 minutes, then the solution was concentrated in vacuo andthe residue diluted with ice water. The precipitate was filtered andwashed with water: crystallization from CH₂ Cl₂ -isopropyl ether gave0.85 g of7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid, ethyl ester, m.p. 252°-255° C., NMR (CDCl₃) δppm. 1.29 (t) (3H,--CH₂ CH₃), 4.12 (bs) (2H,--CH₂ COO--), 4.22 (q) (2H, --CH₂ CH₃), 6.13(s) (1H, C-6 proton), 6.62 (bs) (1H, C-2 proton), 6.85 (d) (1H,β-ethenyl proton), 7.2-7.7 (m) (5H, phenyl protons), 7.75 (d) (1H,β-ethenyl proton); J_(H).sbsb.α_(H).sbsb.β =16 Hz.

By proceeding analogously the following compound was prepared:

6-chloro-7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid, ethyl ester, m.p. 214°-217° C.

EXAMPLE 22

7-trans-[2-(3-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid (0.8 g) was reacted with ethyl iodide (0.65 g) and anhydrous K₂ CO₃(0.65 g) in dimethylformamide (7 ml) under stirring at room temperaturefor 6 hours. After dilution with ice water the precipitate was filteredand washed with water until neutral: crystallization from methanol gave0.55 g pf7-trans-[2-(3-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid, ethyl ester, m.p. 185°-187° C.,

NMR (CDCl₃) δppm. 1.29 (t) (3H, --CH₂ CH₃), 4.14 (s) (2H, --CH₂--COO--), 4.33 (q) (2H, --CH₂ CH₃), 6.16 (s) (1H, C-6 proton), 6.66 (s)(1H, C-2 proton), 6.90 (d) (1H, β-ethenyl proton), 7.30 (dd) (1H, C-5pyridyl proton), 7.75 (d) (1H, C-4 pyridyl proton), 7.89 (ddd) (1H, C-6pyridyl proton), 8.54 (ddd) (1H, C-2 pyridyl proton), 8.87 (dd) (1H,β-ethenyl proton); J_(H).sbsb.α_(H).sbsb.β =16 Hz.

By proceeding analogously the following compound was prepared:

6-chloro-7-trans-[2-(3-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid, ethyl ester, m.p. 242°-243° C.

EXAMPLE 23

6-hydroxy-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one(2.7 g) dissolved in dimethylformamide (40 ml) was reacted with methyliodide (2.12 g) in the presence of anhydrous K₂ CO₃ (2.07 g) understirring at 50° C. for 5 hours.

After cooling the reaction mixture was diluted with ice water and theprecipitate was filtered and washed with water: crystallization from 50%ethanol gave 2.05 g of6-methoxy-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,m.p. 186°-187° C.

EXAMPLE 24

By proceeding according to Examples 21 and 22, the isopropyl and n-butylesters of the following compounds were prepared:

7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

7-trans-[2-(3-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid;

6-chloro-7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid; and

6-chloro-7-trans-[2-(3-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid.

EXAMPLE 25

6-methoxy-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one(2.3 g) was dissolved in ethyl acetate and treated with thestoichiometric amount of gaseous HCl in ether: the precipitate wasfiltered and washed with ethyl acetate to give 2.1 g of6-methoxy-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-onehydrochloride, m.p. 205°-210° C. dec.

By proceeding analogously the following compounds were prepared:

2-chloro-6-methoxy-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-onehydrochloride;

2-chloro-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-onehydrochloride; and

6-methyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-onehydrochloride.

EXAMPLE 26

7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid was treated with the stoichiometric amount of NaHCO₃ in a littlewater at 60° C. for 10 minutes: the solution was concentrated in vacuoto dryness then was diluted with acetone. The precipitate was filteredand washed with acetone:7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid, sodium salt, m.p. >300° C., was obtained.

By proceeding analogously the following compounds were prepared:

7-trans-[2-(3-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid, sodium salt;

6-chloro-7-trans-[2-(3-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid, sodium salt; and

6-chloro-7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid, sodium salt.

EXAMPLE 27

Tablets, each weighing 200 mg and containing 100 mg of the activesubstance are manufactured as follows:

    ______________________________________                                        Compositions (for 10.000 tablets)                                             ______________________________________                                        2-chloro-7-trans-[2-(3-pyridyl)-ethenyl]-5H--                                                            1000 g                                             thiazolo[3,2-a]pyrimidine-5-one                                               Lactose                    710 g                                              Corn starch                237.5 g                                            Talc powder                37.5 g                                             Magnesium stearate         15 g                                               ______________________________________                                    

2-chloro-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one,lactose and a half of the corn starch are mixed; the mixture is thenforced through a sieve of 0.5 mm openings. Corn starch (18 g) issuspended in warm water (180 ml). The resulting paste is used togranulate the powder. The granules are dried, comminuted on a sieve ofsieve size 1.4 mm, then the remaining quantity of starch, talc andmagnesium stearate is added, carefully mixed and processed into tabletsusing punches of 8 mm diameter.

We claim:
 1. A compound having the following general formula (I)##STR32## wherein A completes a bond, thereby providing a double bondbetween the α- and β-carbon atoms, orA represents a --CH₂ --group,thereby providing a cyclopropane ring including the α- and β-carbonatoms; each of R₁ and R₂ independently represents(a) a hydrogen or ahalogen atom; (b) C₁ -C₄ alkyl, cyano or trifluoromethyl; (c) thienyl,pyridyl, biphenyl or naphtyl; (d) a phenyl group, unsubstituted orsubstituted by 1 to 3 substituents chosen from halogen, C₁ -C₄ alkyl,hydroxy, C₁ -C₄ alkoxy, formyloxy, C₂ -C₈ alkanoyloxy, trifluoromethyl,nitro, amino, formylamino, C₂ -C₈ alkanoylamino; (e) a phenyl groupsubstituted by one or two C₁ -C₄ alkylenedioxy groups wherein the oxygenatoms are linked to two adjacent carbon atoms of the phenyl ring; (f) agroup ##STR33## wherein each of R' and R" independently represents ahydrogen atom or a C₁ -C₄ alkyl group; R₃ represents:(a') a hydrogen orhalogen atom; (b') C₁ -C₄ alkyl; (c') hydroxy, formyloxy or C₂ -C₈alkanoyloxy; (d') C₁ -C₄ alkoxy or C₃ -C₄ alkenyloxy; R₄ represents:apyridyl group, which may be unsubstituted or substituted by C₁ -C₄alkyl; and the pharmaceutically acceptable salts thereof.
 2. A compoundof the formula (I) according to claim 1, wherein A is as defined inclaim 8; R₁ is hydrogen, C₁ -C₂ alkyl, trifluoromethyl, carboxymethyl,pyridyl, biphenyl, naphthyl or phenyl, the phenyl being unsubstituted orsubstituted as defined in claim 8; R₂ is hydrogen, chlorine, bromine, C₁-C₂ alkyl, cyano, or phenyl, unsubstituted or substituted as defined inclaim 8; R₃ is hydrogen, chlorine, bromine, C₁ -C₃ alkyl or C₁ -C₂alkoxy; and R₄ represents a pyridyl group unsubstituted or substitutedby a methyl group; and the pharmaceutically acceptable salts thereof. 3.A compound selected from the group consistingof:7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;2-cyano-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;2-chloro-6-methoxy-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;2-chloro-6-methyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;3,6-dimethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;2,3,6-trimethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-methyl-2-phenyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-ethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-methyl-7-trans-[2-(2-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one6-methyl-7-trans-[2-(6-methyl-2-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-methyl-7-trans-[2-(6-methyl-2-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-methyl-7-trans-[2-(2-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-methyl-7-trans-[2-(3-pyridyl)-cyclopropyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;2,6-dichloro-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-chloro-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-chloro-3-methyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-chloro-2,3-dimethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-chloro-3-trifluoromethyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-chloro-3-phenyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-chloro-3-(4-fluoro-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-chloro-3-(4-chloro-phenyl)-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-chloro-3-(4-methyl-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-chloro-3-(2-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-chloro-3-(3-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-chloro-3-(4-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-chloro-3-(2-thienyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-chloro-3-(2-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-chloro-3-(3-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-chloro-3-(4-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;6-chloro-7-trans-[2-(3-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-aceticacid; 3-(4-amino-phenyl)-7-trans-82-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;3-phenyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;3-(4-fluoro-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;3-(4-chloro-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;3-(3-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;3-(4-methoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;3-(3,4-dimethoxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;3-(3,4-ethylendioxy-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;3-(4-biphenylyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;3-(2-naphtyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimdine-5-one;3-(2-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;3-(3-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;3-(4-pyridyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;3-(4-N-acetyl-amino-phenyl)-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;7-trans-[2-(3-pyridyl)-ethenyl]-3-(2-thienyl)-5H-thiazolo[3,2-a]pyrimidine-5-one,andthe pharmaceutically acceptable salts thereof. 4.6-methoxy-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;and the pharmaceutically accceptable salts thereof. 5.2-chloro-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;and the pharmaceutically acceptable salts thereof. 6.6-methyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;and the pharmaceutically acceptable salts thereof. 7.3-(4-methyl-phenyl)-7-trans-[2-(3-pyridyl)ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;and the pharmaceutically acceptable salts thereof. 8.2-methyl-3-phenyl-7-trans-[2-(3-pyridyl)ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one;and the pharmaceutically acceptable salts thereof.
 9. A method for thetreatment of peptic ulcers in a patient comprising administering to thepatient an effective amount of a compound according to claim
 1. 10. Amethod for the treatment of excessive gastric secretion in a patientcomprising administering to the patient an effective amount of acompound according to claim
 1. 11. A method for the treatment ofinflammation in a patient comprising administering to the patient aneffective amount of a compound according to claim
 1. 12. A method forthe treatment of pain in a patient comprising administering to thepatient an effective amount of a compound according to claim
 1. 13. Amethod for the treatment of thrombosis, peripheral vasculopaties andcoronary artery diseases in a patient comprising administering to thepatient an effective amount of a compound according to claim
 1. 14. Apharmaceutical composition containing a suitable carrier and/or diluentand, as an active principle, a compound of formula (I) according toclaim 8, or a pharmaceutically acceptable salt thereof.